Discovery of the First Series of Small Molecule H5N1 Entry Inhibitors

Abstract

The occurrence of highly pathogenic avian influenza virus H5N1 highlights the urgent need for new classes of antiviral drugs. Inhibition of H5N1 entry into cells may be an effective strategy. We report the first three small molecule inhibitors saponins with 3-O-beta-chacotriosyl residue, which showed potent inhibitory activity with IC(50) of 7.22-9.25 microM. The subsequent SAR studies showed the 3-O-beta-chacotriosyl residue was essential for the activity, and the aglycone structure also affected the activity.

Structure–activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors

“…As depicted in Scheme 1, oxidation of methyl ursolate 17 [7] obtained by treating ursolic acid with iodomethane in the presence of pyridinium chlorochromate (PCC) gave the 3-oxo compound 18. Meerwein-Ponndorf reduction of compound 18 afforded 3a-ursolic acid methyl ester 19 as the major product (70%), along with compound 17 (18%) as a minor product.…”

“…In our previous study [7], we have discovered three small molecule H5N1 viral entry inhibitors 1e3 (Fig. 1A) using an efficient HIV-based pseudotyping system to screen a saponin library generated from semisynthesis.…”

“…Structurally, these compounds bear the same bchacotriosyl (a-L-rhamnopyranosyl-(1 / 2)-[a-L-rhamnopyranosyl-(1 / 4)]-b-D-glucopyranosyl) residue that is known as chacotriose. A preliminary structureeactivity relationship (SAR) study [7,8] has indicated that both the chacotriosyl residue and the aglycone moiety of compounds 1e3 are important to the antiviral activity, though several modifications are tolerated at these positions. The 3-O-b-chacotriosyl residue is essential for activity as methylating one or two sugar hydroxyls of the b-chacotriosyl moiety and altering the b-chacotriosyl moiety of compound 1 into a-L-rhamnopyranosyl-(1 / 4)-b-D-glucopyranosyl moiety or a-Lrhamnopyranosyl-(1 / 2)-b-D-glucopyranosyl moiety resulted in the loss of activity.…”

“…In addition, replacement of the aglycone moiety of compound 1 with dihydrochlorogenin, dehydroisoandrosterone or stigmasterine led to the loss of activity except in the case of methyl ursolate (i.e., compound 3), suggesting that the subtle modifications of aglycone may be tolerated without losing antiviral activity. Notably, change of the aglycone moiety of compounds 1 and 2 into pentacyclic triterpene (to afford compound 3) led to slightly stronger inhibition against HA (QH) [7], suggesting that replacement of the aglycone moiety of compound 1 with pentacyclic triterpene can enhance the activity.…”

Convergent Synthesis of Solamargine and Analogues Thereof: Structural Revision of 16‐epi‐Solamargine and Cytotoxic Evaluation

“…3a or azide 3b in turn could be prepared from diosgenin( 5), ar eadily availables pirostanol. Imidate 4 could be disconnected into glucosyl thioglycoside 6, [17] with 2-and 4-hydroxy groups free, and rhamnosyl imidate 7. [18] The strategyw as also applied to synthesis of the analogues 1a-1c of solamargine.…”